U.S. patent number 4,866,074 [Application Number 07/255,728] was granted by the patent office on 1989-09-12 for naphtheridinone- and pyridooxazinone-pyridone compounds, cardiotonic compositions including same, and their uses.
This patent grant is currently assigned to Rorer Pharmaceutical Corporation. Invention is credited to Henry F. Campbell, Donald E. Kuhla, Alfred P. Spada, William L. Studt, Thomas Tucker.
United States Patent |
4,866,074 |
Spada , et al. |
September 12, 1989 |
Naphtheridinone- and pyridooxazinone-pyridone compounds,
cardiotonic compositions including same, and their uses
Abstract
This invention relates to substituted pyridooxazinone and
naphtheridone pyridones which are useful as cardiotonic agents for
the treatment of congestive heart failure, to methods for
increasing cardiac contractility using said compounds, and
pharmaceutical compositions including the same.
Inventors: |
Spada; Alfred P. (Ambler,
PA), Studt; William L. (Harleysville, PA), Campbell;
Henry F. (North Wales, PA), Kuhla; Donald E.
(Doylestown, PA), Tucker; Thomas (North Wales, PA) |
Assignee: |
Rorer Pharmaceutical
Corporation (Fort Washington, PA)
|
Family
ID: |
26724969 |
Appl.
No.: |
07/255,728 |
Filed: |
October 11, 1988 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
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47394 |
May 8, 1987 |
4822794 |
|
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Current U.S.
Class: |
514/300; 514/302;
546/113; 546/116 |
Current CPC
Class: |
C07D
498/04 (20130101) |
Current International
Class: |
C07D
498/00 (20060101); C07D 498/04 (20060101); A61K
031/435 (); C07D 498/04 () |
Field of
Search: |
;546/113,116
;514/300,302 |
References Cited
[Referenced By]
U.S. Patent Documents
|
|
|
3853880 |
December 1974 |
Challier et al. |
3984405 |
October 1976 |
Krapcho |
4119631 |
October 1978 |
Gottschlich et al. |
|
Primary Examiner: Raymond; Richard L.
Parent Case Text
This is a continuation-in-part of U.S. Ser. No. 47,394, filed May
8, 1987, now U.S. Pat. No. 4,822,794, and PCT/US88/01504 filed May
4, 1988.
Claims
We claim:
1. A compound of the formula ##STR12## wherein: A is --C.dbd.or
--N.dbd.;
B is --C.dbd.C--; --C.dbd.N--or --N.dbd.C--;
provided that A or B represents a nitrogen-containing group;
X is --(CR.sub.4 R.sub.5).sub.a --(O).sub.b --(CR.sub.6
R.sub.7).sub.c --;
a and c are 0, 1 or 2;
b is 0 or 1;
provided that a+b+c=1
R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, nitro, halo,
cyano, carbamoyl, alkyl carbamoyl, formyl, aminoalkylene or
amino;
R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are
hydrogen, alkyl, or aralkyl;
R.sub.4 is hydrogen, alkyl, aryl, or aralkyl;
geminal R.sub.6 and R.sub.7 groups may together form a spiro
substituent, --(CH.sub.2).sub.d --, where d is 2 to 5;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 where R is cyano, R.sub.2 is
lower alkyl and R.sub.1, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and
R.sub.7 are hydrogen or lower alkyl.
3. A compound according to claim 2 where
R is cyano;
R.sub.1 is hydrogen;
R.sub.2 is methyl; and
R.sub.3, R.sub.4, R.sub.5, R.sub.6, and R.sub.7 are hydrogen or
methyl.
4. A compound according to claim 3 where
A is --C.dbd.;
B is --C.dbd.N--; and
X is --O--.
5. A compound according to claim 1 where b is 0.
6. A compound according to claim 5 where
A is --C.dbd.; and
B is --C.dbd.N--.
7. A compound according to claim 6 wherein a+c equals 1.
8. A compound according to claim 7 wherein c is 1 and geminal
R.sub.6 and R.sub.7 groups together form a spiro substituent.
9. A compound according to claim 1 which is
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyloxazolo-[4,5-b]pyr
idin-2(3H)-one or a pharmaceutically acceptable salt thereof.
10. A method for increasing cardiotonic contractility in a patient
requiring such treatment which comprises administering to such
patient an effective amount of a compound according to claim 1.
11. A pharmaceutical composition wherein the active ingredient is a
compound according to claim 1 in admixture with a pharmaceutical
carrier.
Description
FIELD OF INVENTION
This invention relates to diazabicyclic substituted pyridones which
are useful as cardiotonic agents for the treatment of congestive
heart failure. This invention also relates to methods for
increasing cardiac contractility using said compounds, and
pharmaceutical compositions including said compounds.
Congestive heart failure is a life-threatening condition in which
myocardial contractility is depressed so that the heart is unable
to adequately pump the blood returning to it. Normal pathologic
sequelae include decreased cardiac output, venous pooling,
increased venous pressure, edema, increased heart size, increased
myocardial wall tension, and eventually cessation of
contractility.
REPORTED DEVELOPMENTS
Drugs which increase the tone of the heart muscle are described as
having positive inotropic activity and are characterized as
cardiotonic agents. Digitalis glycosides have long been used to
increase myocardial contractility and reverse the detrimental
changes seen in congestive heart failure. More recently, dopamine,
dobutamine, and amrinone have been used to provide necessary
inotropic support for the failing heart.
Cardiotonic agents which are described as having positive inotropic
activity include the 5-pyridyl substituted pyridones disclosed in
U.S. Pat. Nos.: 4,004,012; 4,072,746; 4,107,315; 4,137,233;
4,199,586 and 4,271,168; in GB No. 2070606A; and in PCT published
Appl. No. PCT/CH81/00023. Other cardiotonic drugs include the
diazacyclic substituted carbostyril compounds disclosed in U.S.
Pat. Nos. 4,414,390 and 4,415,572, cardiotonic pyridyl substituted
carbostyril compounds disclosed in EPO application Serial No.
84308925.1, and cardiotonic
5-substituted-1,6-naphthyridine-2(1H)-one compounds disclosed in
U.S. Pat. No. 4,657,915.
Cardiotonic bicyclic heteroaryl-5-substituted pyridyl compounds are
disclosed in PCT published application Serial Nos. PCT/US83/01285
and PCT/US87/01489 (WO 88/00188); and, cardiotonic
diazheterocyclic-5-substituted pyridyl compounds are disclosed in
U.S. Pat. Nos. 4,432,979, 4,514,400 and 4,539,321. Each of the
aforementioned is assigned to the same assignee as the present
application.
SUMMARY OF THE INVENTION
The present invention relates to naphtheridone- and
pyridooxazinone-pyridone compounds which are useful for increasing
cardiac contractility in humans and other mammals.
The compounds of the present invention include compounds of Formula
I: ##STR1## wherein:
A is --C.dbd. or --N.dbd.;
B is --C.dbd.C--, --C.dbd.N-- or --N.dbd.C--; provided that A or B
represents a nitrogen-containing group;
X is --(CR.sub.4 R.sub.5).sub.a --(O).sub.b --(CR.sub.6
R.sub.7).sub.c --;
a and c are 0, 1 or 2;
b is 0 or 1;
provided that a+b+c=1, 2 or 3;
R is hydrogen, alkyl, alkoxyalkyl, hydroxyalkyl, nitro, halo,
cyano, carbamoyl, alkyl carbamoyl, formyl, aminoalkylene or amino;
R.sub.1, R.sub.2, R.sub.3, R.sub.5, R.sub.6 and R.sub.7 are
hydrogen, alkyl, or aralkyl; R.sub.4 is hydrogen, alkyl, aryl, or
aralkyl;
geminal R.sub.6 and R.sub.7 groups may together form a spiro
substituent, --(CH.sub.2).sub.d --, where d is 2 to 5; and
pharmaceutically acceptable salts thereof.
This invention relates also to methods for increasing cardiac
contractility using pharmaceutical compositions including an
effective inotropic amount of a compound of Formula I above.
DETAILED DESCRIPTION
As employed above and throughout the disclosure, the following
terms, unless otherwise indicated, shall be understood to have the
following meanings:
"Alkyl" means a saturated aliphatic hydrocarbon which may be either
straight or branched-chained containing from about 1 to about 6
carbon atoms.
"Lower alkyl" means an alkyl group as above, having 1 to about 4
carbon atoms.
"Aralkyl" means an alkyl group substituted by an aryl radical where
aryl means a phenyl or phenyl substituted with one or more
substituents which may be alkyl, alkoxy, amino, nitro, carboxy,
carboalkoxy, cyano, alkyl amino, halo, hydroxy, hydroxyalkyl,
mercaptyl, alkyl mercaptyl, carboalkyl or carbamoyl. The preferred
aralkyl groups are benzyl or phenethyl.
"Alkyl carbamoyl" means a carbamoyl group substituted by one or two
alkyl groups. Preferred groups are the lower alkyl carbamoyl
groups.
"Hydroxyalkyl" means an alkyl group substituted by a hydroxy group.
Hydroxy lower alkyl groups are preferred. Exemplary preferred
groups include hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, and
3-hydroxypropyl.
"Alkoxy" means an alkyl-oxy group in which "alkyl" is as previously
described. Lower alkoxy groups are preferred. Exemplary groups
include methoxy, ethoxy, n-propoxy, i-propoxy and n-butoxy.
"Alkoxyalkyl" means an alkyl group as previously described
substituted by an alkoxy group as previously described.
"Aminoalkylene" means a group of the formula --(CH.sub.2).sub.n
--NH.sub.2 where n is 1 to about 6. The preferred groups are the
lower alkylene amino groups wherein lower alkylene groups are of 1
to about 4 carbon atoms. The most preferred amino alkylene group is
aminomethylene.
Certain of the compounds of the present invention may exist in
enolic or tautomeric forms, and all of these forms are considered
to be included within the scope of this invention.
The compounds of this invention may be useful in the form of the
free base, in the form of salts and as a hydrate. All forms are
within the scope of the invention. Acid addition salts may be
formed and are simply a more convenient form for use; and in
practice, use of the salt form inherently amounts to use of the
base form. The acids which can be used to prepare the acid addition
salts include preferably those which produce, when combined with
the free base, pharmaceutically acceptable salts, that is, salts
whose anions are non-toxic to the animal organism in pharmaceutical
doses of the salts, so that the beneficial cardiotonic properties
inherent in the free base are not vitiated by side effects
ascribable to the anions. Although pharmaceutically acceptable
salts of said basic compound are preferred, all acid addition salts
are useful as sources of the free base form even if the particular
salt per se is desired only as an intermediate product as, for
example, when the salt is formed only for purposes of purification
and identification, or when it is used as an intermediate in
preparing a pharmaceutically acceptable salt by ion exchange
procedures. Pharmaceutically acceptable salts within the scope of
the invention are those derived from the following acids: mineral
acids such as hydrochloric acid, sulfuric acid, phosphoric acid and
sulfamic acid; and organic acids such as acetic acid, citric acid,
lactic acid, tartaric acid, malonic acid, methanesulfonic acid,
ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,
cyclohexylsulfamic acid, quinic acid, and the like. The
corresponding acid addition salts comprise the following:
hydrochloride, sulfate, phosphate, sulfamate, acetate, citrate,
lactate, tartarate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate and
quinate, respectively.
The acid addition salts of the compounds of this invention are
prepared either by dissolving the free base in aqueous or
aqueous-alcohol solution or other suitable solvents containing the
appropriate acid and isolating the salt by evaporating the
solution, or by reacting the free base and acid in an organic
solvent, in which case the salt separates directly or can be
obtained by concentration of the solution.
A preferred class of cardiotonic compounds of this invention is
described by Formula I wherein the bicyclic ring of the molecule is
represented by Formulae IIa-IIc, IIIa-IIIc or IVa-IVc, presented
below: ##STR2## wherein:
R.sub.3, R.sub.4, R.sub.5, R.sub.6 and R.sub.7 are as described
above and a and c are 1 or 2.
A more preferred class of compounds are of Formula I-IV above,
wherein R is cyano, R.sub.2 is lower alkyl and R.sub.1, R.sub.3,
R.sub.4, R.sub.5, R.sub.6, R.sub.7 are hydrogen or lower alkyl.
Most preferred compounds are those disclosed by Formula I, wherein
R is cyano, R.sub.1 is hydrogen, R.sub.2 is methyl and R.sub.3
through R.sub.7 are hydrogen or methyl.
A special embodiment of the invention comprises compounds of
Formula IIIc where b+c add up to 2.
A further special embodiment comprises compounds of Formula I where
R.sub.6 and R.sub.7 form a spiro ring system, two examples of which
are shown by Formula V and Va below: ##STR3##
Compounds of this invention may be prepared by constructing the
pyridone ring substituent on the bicyclic portion of the compound
as shown below in Scheme I. ##STR4##
Halogenation of a compound of Formula VI results in the
corresponding halogentated product VII. Bromination is a preferred
reaction which occurs on the pyrido ring of the bicyclic compound
in the position para to the nitrogen of the lactam. Bromination can
be carried out with bromination reagents known in the art. A
preferred method is N-bromosuccinimide in a polar, non-protic
solvent such as DMF. Subsequent alkylation or aralkylation of the
lactam nitrogen with an appropriate alkylating agent results in the
adduct of Formula VIII, which is oxopropylated by treatment with an
acylated isopropenyl reagent and catalyst. A preferred catalytic
system comprises the use of tri-o-tolylphosphine, palladium
acetate, and tributyltin methoxide. Preferred reaction conditions
comprise using a non-polar solvent such as benzene and heating the
reaction to a temperature which results in the preparation of the
product in a reasonably short period of time of about 10 minutes to
about two days. A preferred temperature range is about 75.degree.
to about 80.degree. C. Condensation of the compound of Formula IX
with N,N-dimethylformamide dimethylacetal results in the alpha,
beta unsaturated keto-compound X. Cyclization to the compound of
Formula Ia is accomplished by treatment with an appropriate
amido-containing nucleophile which adds 1,2 to the unsaturated
ketone and condenses with the ketone eliminating dimethylamine and
water. A preferred nucleophile is sodium cyanoacetamide which may
be prepared by the reaction of sodium hydride with cyanoacetamide
or sodium ethoxide in ethanol. Compound X may also be condensed
with nitroacetamide resulting in the compound of Formula I where R
is NO.sub.2. The cyclization reaction is conducted preferably at
elevated temperature such as 70.degree. to about 90.degree. C.,
under inert conditions in a polar medium such as DMF or
ethanol.
The cyano substituent in Formula Ia may be converted to other
substituents defined for R in Formula I. For example the cyano
group may be hydrolyzed to the acid which in turn can be esterified
or converted to the amide. The ester may be converted by known
methods to formyl which in turn can be reduced to the alkyl or
hydroxyalkyl substituent. The alkoxyalkyl may be formed from the
hydroxyalkyl.
The nitro-containing compound may be reduced to the amino compound
from which the hydroxy and halo substituted compounds may be
formed. These methods and reaction conditions would vary, of
course, depending on the desired substituent and the substituent
present, and are known to one skilled in the art.
The starting materials useful for the preparation of the compounds
of this invention are known, can be prepared by known methods or
prepared in accordance with the reaction sequences described below.
For compounds of Formula I wherein b is 1, the bicyclic portion of
the compound may be prepared according to the following reaction
sequences.
When 2-amino-3-hydroxypyridine is treated with sodium hydride
followed by ring closure with a .alpha.-haloacetate ester of the
formula ##STR5## the pyridooxazinones are formed. ##STR6## When the
seven member-containing bicyclic ring is desired, the reaction is
carried out using the halopropionate as show below. ##STR7##
The five member-containing bicyclic ring is prepared by reacting
2-amino-3-hydroxypyridine with either phosgene or
N,N-carbonyldiimidazole as shown below. ##STR8##
Those compounds where the oxygen atom of the pyrido-oxazinone ring
is not directly on the pyridine ring are prepared from a
2-aminonicotinic acid or ester, reducing the latter to the
corresponding alcohol and cyclizing as above.
These reactions are depicted in Schemes II and IIa below.
##STR9##
When the starting pyridine is 3-amino-4-hydroxypyridine or
2-hydroxy-3-aminopyridine then the corresponding pyridooxazinone is
prepared as shown below. ##STR10##
Compounds wherein R.sub.3 is other than hydrogen are prepared from
N-R.sub.3 -substituted amino-pyridines.
For compounds of Formula I wherein b is 0, the bicyclic portion of
the compounds may be prepared according to one of the reaction
sequences depicted in Scheme III below. Treatment of the
3-carbonyl-2-trimethylmethylamidopyridine compound depicted in
Scheme III with a triphenylphosphine ylide reagent yields the
unsaturated ylide addition product. The ylide chosen for the
addition reaction may include R.sub.6 and R.sub.7 substituents
other than hydrogen. Furthermore, the R.sub.8 substituent on the
ylide determines the size of the resultant saturated ring of the
bicylclic end product as shown in Scheme III. Hydrogenation of the
ylide addition product and acidic cylcization to the lactam
provides the bicyclic system. ##STR11##
N-alkylation and halogenation of the bicyclic ring proceeds in the
same manner as described for the oxygen-containing bicyclic rings
discussed above.
Introduction of a spiro group into the bicyclic rings wherein the
carbon atom alpha to the lactam carbonyl is unsubstituted is
accomplished by reacting the intermediate compound of Formulae VIII
with a strong base such as lithium diisopropyl amide and a suitable
dibromoalkane such as 1,2-dibromoethane or 1,4-dibromobutane.
Specific examples of the preparation of compounds of this invention
are described below.
EXAMPLE 1
THE PREPARATION OF 7-[3'-CYANO-6'-METHYL-2
-OXO-(1H)PYRIDIN-5'-YL]-4-METHYL-2H-PYRIDO[3,2-b]-1,4-OXAZIN-3(4H)-ONE
Step 1. 7-Bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
To a solution of 5.6 g 2H-pyrido[3,2-b]-1,4-oxazin-3-(4H)-one
dissolved in 85 ml of DMF under nitrogen is added 7.96 g NBS in 50
ml of DMF. This is allowed to stir at room temperature overnight.
To this is added 35 ml of water and chilled. The solid material
which separates is filtered and washed with 3.times.100 ml H.sub.2
O. This is then dried in a vac oven at 70.degree. C. and then used
directly in the next step.
Step 2. 4-Methyl-7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
To a suspension of 5 g of
7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (0.022 mole) in 90 ml
of THF is added 24 ml of LiN(TMS).sub.2 (0.024 mole) in THF. The
homogenous solution is maintained under nitrogen at room
temperature for 20 min., 3.03 g (0.024 mole) of dimethylsulfate is
added and the reaction mixture allowed to stir overnight. The
reaction mixture is then quenched with 20 ml of sat. ammonium
chloride and extracted with 3.times.80 ml ethyl acetate. The ethyl
acetate is then washed with 3.times.30 ml sat. ammonium chloride,
dried over sodium sulfate and concentrated to obtain off white
product which is used directly in the next step.
Step 3.
4-Methyl-7-(2'-oxopropyl)-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
4-Methyl-7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one (3 g) (0.012
mole) in 80 ml of benzene is treated with 365 mg
tri-o-tolylphosphine, 138 mg palladium acetate, 1.87 g (0.018 mole)
of isopropenyl acetate and 5.9 g (0.18 mole) of tributyltin
methoxide. The mixture is heated to 70.degree. C. for 25 hours. The
reaction mixture is then quenched with 20 ml sat. ammonium chloride
and diluted with 50 ml ethyl acetate. The organic phase separates,
dried over sodium sulfate and concentrated to dryness. The residue
is dissolved in methylene chloride, washed with sat. KF solution,
filtered through a cotton plug, dried over sodium sulfate and
concentrated to dryness to obtain crude product. This is
chromatographed using 200.times.60 mm SiO.sub.2,EtOAc (100%) as
eluent. The desired product is identified by NMR and used directly
in the next step.
Step 4. 4-Methyl-7-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-2
H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
To 1.05 g (0.0047 mole) of
4-methyl-7-(2'-oxopropyl)-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
suspended in 10 ml of dimethylformamide dimethylacetal is added 1
ml of pyridine. This is then heated under nitrogen at 70.degree. C.
for 5 hours. The reaction mixture is then concentrated in vacuo to
leave an dark oily solid. Trituration with methylene chloride gives
a pale yellow solid which is filtered off and identified to be
desired product by NMR. This is then used directly in the next
step.
Step 5.
7-[3'-Cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido(3,2-b]-
1,4-oxazin-3(4H)-one
Sodium hydride (87 mg/oil) is washed with pet. ether and suspended
in 4 ml of DMF under nitrogen. To this is added 166 mg of
cyanoacetamide in 3 ml of DMF and the mixture stirred for about 5
min. A solution of 500 mg of
4-methyl-7-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-2H-pyrido[3,2-b]-1,4-o
xazin-3(4H)-one in 4 ml of DMF is added to the mixture and heated
under nitrogen at 80.degree. C. for 4.5 hours. This is then diluted
with 15 ml of sat. ammonium chloride and extracted with 4.times.40
ml of ethyl acetate, dried over sodium sulfate and concentrated in
vacuo. (M.P. 350.degree. C.)
Calc'd. C, 59.36; H, 4.25; N, 18.46.
Found C, 59.44; H, 4.32; N, 18.56.
EXAMPLE 2
When 2H-pyrido[3,2-b]-1,4-oxazin-3-(4H)-one of Example 1, Step 1 is
replaced with the compounds of Table I below, then the
corresponding product is obtained.
Table I
2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one
2H-pyrido[4,3-b]-1,4-oxazin-3(4H)-one
2H-pyrido[2,3-b]-1,4-oxazin-3(4H)-one
4H-pyrido[2,3-d][1,3]oxazin-2(1H)-one
4H-pyrido[3,4-d][1,3]oxazin-2(1H)-one
4H-pyrido[3,2-d][1,3]oxazin-2(1H)-one
oxazolo[4,5-b]pyridin-2(3H)-one
oxazolo[4,5-c]pyridin-2(3H)-one
oxazolo[5,4-b]pyridin-2(3H)-one
2,3-dihydropyrido[3,2-b][1,4]oxazepin-4(5H)-one
2,3-dihydropyrido[4,3-b][1,4]oxazepin-4(5H)-one
2,3-dihydropyrido[2,3-b][1,4]oxazepin-4(5H)-one
3,5-dihydropyrido[2,3-e]-1,4-oxazepin-2-(1H)-one
3,5-dihydropyrido[3,4-e]-1,4-oxazepin-2-(1H)-one
3,5-dihydropyrido[3,2-e]-1,4-oxazepin-2-(1H)-one
4,5-dihydropyrido[2,3-d]-1,3-oxazepin-2(1H)-one
4,5-dihydropyrido[3,4-d]-1,3-oxazepin-2(IH)-one
4,5-dihydropyrido[3,2-d]-1,3-oxazepin-2(1H)-one
EXAMPLE 3
The Preparation of
6-[3'-Nitro-6'-Methyl-2-Oxo-(1H)Pyridin-5'-YL]-3-Methyl-Oxazolo[4,5-b]Pyri
din-2(3H)-One
Step 1. 6-Bromo-oxazolo[4,5-b]pyridin-2(3H)-one
To a solution of 5.07 g oxazolo[4,5-b]pyridin-2(3H)-one dissolved
in 85 ml of DMF under nitrogen is added 7.46 g NBS in 50 ml of DMF.
This is allowed to stir at room temperature overnight. To this is
added 35 ml of water and chilled. The solid material which
separates is filtered and washed with 3.times.100 ml H.sub.2 O.
This is then dried in a vac oven at 70.degree. C. and then used
directly in the next step.
Step 2. 3-Methyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one
To a suspension of 4.7 g of 6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one
(0.022 mole) in 90 ml of THF is added 24 ml of LiN(TMS).sub.2
(0.024 mole) in THF. The homogenous solution is maintained under
nitrogen at room temperature for 20 min., 3.03 g (0.024 mole) of
dimethylsulfate is added and the reaction mixture allowed to stir
overnight. The reaction mixture is then quenched with 20 ml of sat.
ammonium chloride and extracted with 3.times.80 ml ethyl acetate.
The ethyl acetate is then washed with 3.times.30 ml sat. ammonium
chloride, dried over sodium sulfate and concentrated to obtain off
white product which is used directly in the next step.
Step 3.
3-Methyl-6-(2'-oxopropyl)oxazolo[4.5-b]pyridin-2-(3H)-one
3-Methyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one (2.58 g) (0.012
mole) in 80 ml of benzene is treated with 365 mg
tri-o-tolylphosphine, 138 mg palladium acetate, 1.87 g (0.018 mole)
of isopropenyl acetate and 5.9 g (0.18 mole) of tributyltin
methoxide. This is sealed in a high pressure tube and heated to
70.degree. C. for 25 hours. The reaction mixture is then quenched
with 20 ml sat. ammonium chloride and diluted with 50 ml ethyl
acetate. The organic phase separates, dried over sodium sulfate and
concentrated to dryness. The residue is dissolved in methylene
chloride, washed with sat. KF solution, filtered through a cotton
plug, dried over sodium sulfate and concentrated to dryness to
obtain crude product. This is chromatographed using 200.times.60 mm
SiO.sub.2, EtOAc (100%) as eluent. The desired product is
identified by NMR and used directly in the next step.
Step 4. 3-Methyl-6-[1'-N,N-dimethylamino-3'-oxobuten-2'
-yl]-oxazolo(4,5-b]pyridin-2(3H)-one
To 1.47 g (0.007 mole) of
3-methyl-6-(2'-oxopropyl)oxazolo[4,5-b]pyridin-2(3H)-one suspended
in 15 ml of dimethylformamide dimethylacetal is added 1.5 ml of
pyridine. This is then heated under nitrogen at 70.degree. C. for 5
hours. The reaction mixture is then concentrated in vacuo to leave
a dark oily solid. Trituration with methylene chloride gives a
solid which is filtered off and identified to be desired product by
NMR. This is then used directly in the next step.
Step. 5.
6-[3'-Nitro-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyl-oxazolo[4,5-b]pyr
idin-2(3H)-one
Sodium hydride (174 mg/oil) is washed with pet. ether and suspended
in 10 ml of DMF under nitrogen. To this is added 330 mg of
nitroacetamide in 6 ml of DMF and the mixture stirred for about 5
min. A solution of 940 mg of
3-methyl-6-[1'-N,N-dimethylamino-3'-oxobuten-2'-yl]-oxazolo[4,5-b]pyridin-
2(3H)-one in 10 ml of DMF is added to the mixture and heated under
nitrogen at 80.degree. C. for 4.5 hours. This is then diluted with
30 ml of sat. ammonium chloride and extracted with 4.times.75 ml of
ethyl acetate, dried over sodium sulfate and concentrated in
vacuo.
EXAMPLE 4
When nitroacetamide is replaced in Example 3, Step 5 by
cyanoacetamide then the product prepared is
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyl-oxazolo[4,5-b]pyr
idin-2(3H)-one.
EXAMPLE 5
When dimethylsulfate is replaced in Examples 1 and 3, Step 2, with
benzylbromide, then
4-benzyl-7-bromo-2H-pyrido[3,2-b]-1,4-oxazin-3(4H)-one and
3-benzyl-6-bromo-oxazolo[4,5-b]pyridin-2(3H)-one are produced.
EXAMPLE 6
Following the procedures of Examples 1-5, the following compounds
may be prepared:
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[4,3-b]-1
,4-oxazin-3(4H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[2,3-b]-1
,4-oxazin-3(4H)-one.
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyloxazolo[4,5-b]pyrid
in-2(3H)-one.
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyloxazolo[4,5-c]pyrid
in-2(3H)-one.
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3-methyloxazolo[5,4-c]pyrid
in-2(3H)-one.
6-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-1-methyl-4H-pyrido[2,3-d][1
,3]oxazin-2(1H)-one.
8-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-5-methyl-2,3-dihydropyrido[
3,2-b][1,4]oxazepin-4(5H)-one.
8-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-5-methyl-2,3-dihydropyrido[
4,3-b][1,4]oxazepin-4(5H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-1-methyl-3,5-dihydropyridin
[2,3-e]-1,4-oxazepin-4(1H)-one.
7-[3'-amino-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[3,2-b]-1
,4-oxazin-3(4H)-one.
7-[3'-chloro-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[3,2-b]-
1,4-oxazin-3(4H)-one.
7-[3'-methoxymethyl-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-2H-pyrido[
3,2-b]-1,4-oxazin-3(4H)-one.
7-[3',6'-dimethyl-2'-oxo-(1H)pyridin-5'-yl]-4-methyl-H-pyrido[3,2-b]-1,4-ox
azin-3(4H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-benzyl-2H-pyrido[3,2-b]-1,4
-oxazin-3(4H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-4-ethyl-2H-pyrido[3,2-b]-1,
4-oxazin-3(4H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2H-pyrido[3,2-b]-1,4-oxazin
-3(4H)-one.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2,2,4-trimethyl-2H-pyrido[3
,2-b]-1,4-oxazin-3(4H)-one.
(M.P. >300.degree. C.)
Calc'd. C, 61.93; H, 4.55; N, 18.06. Found C, 61.64; H, 4.95; N,
17.14. Confirmed by high resolution mass spec.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2-methyl-2H-pyrido[3,2-b]-1
,4-oxazin-3(4H)-one.
(M.P. >310.degree. C.)
Calc'd. C, 62.95; H, 4.47; N, 17.27. Found C, 62.61; H, 5.18; N,
16.94.
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2,4-dimethyl-2H-pyrido[3,2-
b]-1,4-oxazin-3(4H)-one.
(M.P. >300.degree. C.)
Calc'd C, 61.04; H, 4.64; N, 17.79. Found C, 61.08; H, 4.72; N,
17.65. As the quarterhydrate
7-[3'-cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-2-phenyl-2H-pyrido[3,2-b]-1
,4-oxazin-3(4H)-one.
(M.P. 224.degree.-246.degree. C.)
Calc'd. C, 66.92; H, 4.42; N. 14.87. Found C, 66.81; H, 4.84; N,
14.52. As the quarterhydrate
EXAMPLE 7
The Preparation of
6-[3'-Cyano-6'-Methyl-2'-Oxo-(1H)Pyridin-5'-YL]-3,4-Dihydro-1-Methyl-1,8-N
aphtheridin-2(1H)-One
Step 1. 2-(Pivaloylamino)pyridine
A solution of pivaloyl chloride (96 g) in methylene chloride (200
ml) is added dropwise to a cooled mixture of 2-aminopyridine (50 g)
and triethylamine (108 g) in methylene chloride (650 ml). The
reaction mixture is stirred overnight at RT and poured into water
which is basified and the organic layer separated and concentrated
in vacuo. Hexane is added to the oil which results in the
precipitation of a crystalline solid which is filtered and the
solid taken up in aqueous acid. The desired pyridine compound is
recrystallized as a white crystalline solid.
Step 2. 3-Formyl-2-(pivaloylamino)pyridine
N-Butyl lithium (112 ml) is added dropwise to a stirred solution of
the pyridine prepared according to step 1 (20 g) in THF (250 ml) at
-78.degree. C. The reaction mixture is warmed to 0.degree. C. for
about 4 hours and cooled to -78.degree. C. Dimethyl formamide (30
ml) is added to the cooled reaction mixture and the mixture stirred
overnight at RT. The reaction mixture is quenched with sat'd
aqueous NH.sub.4 Cl and diluted with ethyl acetate. The organic
layer is separated, concentrated and treated with aqueous acid. The
aqueous layer is washed with ethyl acetate, brought to a neutral pH
and extracted with ethyl acetate. The organic extract is dried,
concentrated in vacuo and cooled, resulting in the formation of a
crystalline material which is further purified on a silica gel
column to afford a white crystalline solid used in the next
step.
Step 3. 3-(2-Carbomethoxyvinyl)-2-(pivaloylamino)-pyridine
A solution of the formyl compound of step 2. above (9.8 g) in
methylene chloride (100 ml) is added dropwise to a solution of
carbomethoxymethylide triphenylphosphine (16 g) in methylene
chloride (125 ml). The reaction mixture is stirred at reflux
overnight, cooled to RT, concentrated in vacuo and petroleum ether
added. The ethereal solution is cooled resulting in the
precipitation of the desired material as a white crystalline solid,
M.P 148.degree.-150.degree. C. Step 4.
3,4-Dihydro-1,8-naphtheridin-2(1H)-one
A solution of the carbomethoxy vinyl compound of step 3. above (9
g), 10% Pd on C in ethanol (400 ml) is introduced into a Parr
apparatus and stirred under hydrogen until the reaction is
complete. The reaction mixture is filtered, the filtrate
concentrated in vacuo, and the residue dissolved in 6N HCl and
stirred at 110.degree. C. overnight. The reaction mixture is
neutralized, extracted with chloroform and dried, filtered and
concentrated in vacuo. The resulting solid is chromatographed on
silica gel resulting in a purified white crystalline product, M.P.
160.degree.-162.degree. C.
Step 5. 6-Bromo-3,4-dihydro-1,8-naphtheridin-2(1H)-one
A solution of N-bromosuccinimide (3.7 g) in dimethyl formamide (70
ml) is added dropwise to a stirring solution of the naphtheridine
of step 4. above maintained at about -10.degree. C. The reaction
mixture is warmed to RT and stirred overnight. Water is added to
the mixture and the resulting suspension is stirred for 15 min.,
filtered, the filtered solid washed with water and recrystallized
from DMF to yield the desired product as a white crystalline
solid.
Step 6. 6-Bromo-3,4-dihydro-1-methyl-1,8-naphtheridin-2(1H)-one
A 1M solution of lithium bistrimethylsilylamide in THF (6.6 ml) is
added dropwise to a stirring solution of the bromide from step 5
above (1.2 g) in THF (100 ml) at 0.degree. C. The mixture is
allowed to warm to RT and stirred for about 1 hour. Dimethyl
sulfate (0.8g) is added to the mixture which is stirred for about 2
hours. The reaction is quenched with sat'd aqueous NH.sub.4 Cl and
the organic layer is separated, washed with sat'd NH.sub.4 Cl
solution, concentrated in vacuo, and the residue taken up in
chloroform. The chloroform solution is washed with water, dried,
concentrated and chromatographed on silica gel to yield the desired
product as a clear white crystalline solid,
M.P.=78.degree.-80.degree. C.
Step 7.
6-(2-oxopropyl)-3,4-dihydro-1-methyl-1,8-naphtheridin-2(1H)-one
Para-triorthotolylphosphine (0.1 g), palladium acetate (0.05 g),
2-acetoxypropene (0.6 g) and tributyltin methoxide (2g) are added
to a solution of the bromide from step 6 above (1 g) in benzene (40
ml), and the resulting reaction mixture is stirred under N.sub.2 at
80.degree. C. for about 2.5 hours. The mixture is filtered,
concentrated in vacuo, and the residue taken up in acetonitrile.
The solution is filtered and the filtrate washed with hexanes. The
acetonitrile layer is dried, filtered and concentrated in vacuo
yielding the desired product as a crystalline solid,
M.P.=93.degree.-95.degree. C.
Step 8.
6-(1-N,N'-Dimethylamino-3-oxobuten-2-yl)-2-oxopropyl)-3,4-dihydro-1-methyl
-1,8-naphtheridin-2(1H)-one
Dimethylformamide dimethylacetal (4.6 ml) is added to a solution of
the compound of step 7. above (0.7 g) in methylene chloride (25 ml)
and the reaction mixture stirred under nitrogen overnight. The
mixture was evaporated yielding the desired product as an oil which
is used as is in the next step.
Step 9.
6-[3'-Cyano-6'-methyl-2'-oxo-(1H)pyridin-5'-yl]-3.4-dihydro-1-methyl-1,8-n
aphtheridin-2(1H)-one
A solution of the dimethylamino enamine of step 8 above (0.7 g) in
absolute ethanol (45 ml) is added to a mixture prepared by adding a
21% solution of sodium methoxide in ethanol(1.5 ml) to a solution
of cyanoacetamide (0.3 g) in ethanol (25ml). The reaction mixture
is stirred at reflux under nitrogen overnight. The mixture is
cooled to RT, concentrated in vacuo, and chromatographed on silica
gel. The fractions including the solid desired product are
recrystallized twice from isopropyl alcohol affording the desired
product as a crystalline material, M.P.=230.degree. C. (dec).
Calc'd. C, 63.73; H, 4.94; N, 18.58. Found C, 63.84; H, 4.94; N,
18.30.
The compounds of Formula I possess positive inotropic activity and
are useful as cardiotonic agents in the treatment of humans and
other mammals for cardiac disorders including congestive heart
failure. The effectiveness of the compounds of this invention a
inotropic agents may be determined by the following pharmacologic
tests which evaluate the change in cardiac contractile force upon
exposure to a dose of said compounds. The ganglionic-beta blocked
anesthetized dog procedure is one such standard test procedure; the
inotropic results of this procedure generally correlate with the
inotropic activity found in human patients.
Ganglionic-Beta Blocked Anesthetized Dog Procedure
Adult mongrel dogs of either sex weighing 10 to 16 kg are fasted
overnight, anesthetized with pentobarbital sodium 35 mg/kg, i.v.
intubated, respired with room air using a Harvard respirator, and
instrumented surgically to monitor myocardial contractile force,
heart rate, arterial pressure, aortic flow and EKG limb lead II.
The aforesaid measurements are recorded continuously on a strip
chart recorder.
Myocardial contractile force is monitored by a Walton-Brodie strain
gauge sutured to the left ventricular myocardium parallel to the
left anterior descending coronary artery. Arterial pressure is
measured using a fluid-filled catheter attached to a pressure
transducer introduced via the right femoral artery and positioned
in the thoracic aorta. Mean arterial pressure is determined by
electronically clamping the pulsatile pressure signal. Aortic flow
is monitored using a precalibrated, noncanulating electromagnetic
flow probe positioned around the thoracic aorta. Heart rate is
monitored using a cardiotachometer triggered by the QRS complex of
the limb lead II EKG. The right femoral vein is cannulated for
intravenous infusion of drugs. Body temperature is maintained at
37.degree. C.
Following a 30 min postsurgical stabilization period, control
valves are recorded. Myocardial depression is induced by ganglionic
and beta receptor blockade. Initially, the responsiveness of the
autonomic nervous systems is assessed by performing a 30 sec
bilateral carotid occlusion (BCO). Ten minutes later, a saline
solution of isoproterenol 0.3 mg/kg, i.v. is administered to assess
beta receptor integrity. Ten minutes after that, a saline solution
of mecamylamine 2 mg/kg, i.v. is infused, followed by a saline
solution of propranolol 1 mg/kg, i.v. plus 0.3 mg/kg/hr. Twenty
minutes later, a second BCO is performed to demonstrate ganglionic
blockade followed by a second injection of saline isoproterenol 0.3
mg/kg, i.v. to demonstrate beta blockade. Ten minutes later, the
test compound or vehicle is administered intravenously in ascending
doses at 30 min intervals at 1.5 ml/min in a total volume of 3.5
ml. On completion of the experiment, both BCO and isoproterenol
challenges are repeated to verify ganglionic and beta blockade.
The results of the blocked dog test show that compounds of the
present invention increase contractile force and heart rate, and
aortic blood flow in a dose related manner while maintaining
arterial pressure.
Additional test procedures which have been found to be an efficient
means for ascertaining the inotropic activity of the compounds of
this invention are described below.
Guinea Pig Atria Inotropic Screening Concentrations
Guinea pigs are stunned by a sudden blow to the head; their chests
are opened and hearts excised and placed in Kreb.varies.s medium
(concentrations, mM: NaCl, 118.39; KCl, 4.70; MgSO.sub.4, 1.18;
KH.sub.2 PO.sub.4, 1.18; NaHCO.sub.3, 25.00; glucose, 11.66 and
CaCl.sub.2, 1.25 gassed with a mixture of 95% O.sub.2. Left atria
are removed and inserted into warmed (33.degree. C.) double
jacketed tissue chambers containing oxygenated Kreb's medium (as
above). The upper end of each tissue is attached to a Statham
Universal Transducing Cell via a Statham Microscale Accessory.
Resting tension on each tissue is set at 1 g and adjusted
periodically.
Massive field stimulation is achieved via a pair of platinum or
silver electrodes placed on opposite sides of the tissue.
Electrodes are made from 2-gauge silver wire wound into a tight
coil approximately 12-14 mm in diameter. Electrodes are connected
to a Grass stimulator via Grass constant current unit. Tissues are
driven at 90 pulses per minute with 5 msec duration at current
levels 20% greater than threshold for continuous beat.
Cumulative concentrations of test drugs are added to the tissue
bath at intervals sufficient to allow developed tension to peak at
a new level.
The increase in developed tension is each tissue for each compound
concentration is measured, and the results are averaged and used to
construct cumulative concentration-response curves. Slopes for
these regressions calculated via the method of Finney (1971) are
compared using Student's t-test.
The following in vitro method is another means for measuring the
inotropic potency of the present compounds. This method is a
modification of the enzyme inhibition method reported by Thompson
and Appleman (1970) and Thompson et al. (1974), and is believed to
correlate to in vivo inotropic activity in humans.
Inhibition of Peak III cAMP Phosphodiesterase Activity
The test compounds are included in media comprising a radioactivity
labeled substrate (.sup.3 H-cyclic nucleotide) such as adenosine
3':5'-monophosphate (cyclic AMP) and quanine-3':5'-nucleotidease
isolate from a dog heart. The inhibition of the enzyme hydrolysis
of the 5'-nucleotide product of the cNUC-PDEase to the
corresponding nucleoside is measured by separating the charged,
unhydrolyzed substrate from the uncharged hydrolysis product.
Separation may be achieved either chromatographically from the
uncharged nucleoside product of the assay with ion exchange resin
so that it is not quantitated with the liquid scintillation
counter.
Anesthetized Dog Procedure
Male mongrel dogs are anesthetized with pentobarbital (35 mg/kg,
i.v.) and intubated. Femoral artery and veins are cannulated for
measurement of blood pressure and injection of compounds,
respectively. A catheter connected to a Statham transducer is
inserted into the left ventricle via the right carotid artery for
measurement of left ventricular pressure, left ventricular end
diastolic pressure and dP/dt. Lead II ECG and heart rate are also
monitored. All parameters are measured on a Beckman Dynagraph.
Two additional test procedures which have been found to be an
efficient means for ascertaining the inotropic activity of the
compounds of this invention are described below.
Conscious Instrumented Dog
Female mongrel dogs (18.0-18.5 kg) are anesthetized with sodium
pentobarbital (35 mg/kg, i.v., supplemented as necessary during
surgery) intubated and connected to a Harvard respirator. The left
side of the chest is opened at the fifth intercostal space, and a
Konigsberg transducer inserted into the left ventricle through a
puncture at the apex and secured. A fluid-filled polyethylene
catheter is inserted into the left atrium through a puncture wound
and secured for measurement of left atrial pressure. A second
fluid-filled catheter is inserted into the aorta for measurement of
blood pressure and heart rate and secured to the vessel wall. The
two catheters and the Konigsberg transducer cable are passed out of
the chest through the seventh intercostal space and advanced
subcutaneously to the back of the neck and passed through the skin.
The fluid-filled catheters are filled with heparinized 50% dextrose
solution, and the chest is closed and evacuated.
The dog is trained and acclimated to its environment and the
presence of personnel during the experiment.
The dogs are fasted overnight before either intravenous or oral
administration of the compound. On a test day, the dog is placed in
a sling and connected to a recorder (Gould Instruments or Grass
Instruments) for measurement of left ventricular pressure, left
ventricular dP/dt.sub.max, blood pressure, heart rate (from the
blood pressure signal), and the lead II electrocardiogram. The
compound is administered both intravenously and orally (liquid and
soft gelatin capsule forms) in different experiments and blood
samples were taken for determination of blood levels of the
compound.
The compounds of this invention can be normally administered orally
or parenterally, in the treatment of cardiac disorders such as
heart failure in humans or other mammals.
The compounds of this invention, preferably in the form of a salt,
may be formulated for administration in any convenient way, and the
invention includes within its scope pharmaceutical compositions
containing at least one compound according to the invention adapted
for use in human or veterinary medicine. Such compositions may be
formulated in a conventional manner using one or more
pharmaceutically acceptable carriers or excipients. Suitable
carriers include diluents or fillers, sterile aqueous media and
various non-toxic organic solvents. The compositions may be
formulated in the form of tablets, capsules, lozenges, troches,
hard candies, powders, aqueous suspensions, or solutions,
injectable solutions, elixirs, syrups and the like and may contain
one or more agents selected from the group including sweetening
agents, flavoring agents, coloring agents and preserving agents, in
order to provide a pharmaceutically acceptable preparation.
The particular carrier and the ratio of inotropic active compound
to carrier are determined by the solubility and chemical properties
of the compounds, the particular mode of administration and
standard pharmaceutical practice. For example, excipients such as
lactose, sodium citrate, calcium carbonate and dicalcium phosphate
and various disintegratants such as starch, alginic acid and
certain complex silicates, together with lubricating agents such as
magnesium stearate, sodium lauryl; sodium lauryl sulphate and talc,
can be used in producing tablets. For a capsule form, lactose and
high molecular weight polyethylene glycols are among the preferred
pharmaceutically acceptable carriers. Where aqueous suspensions for
oral use are formulated, the carrier can be emulsifying or
suspending agents. Diluents such as ethanol, propylene glycol,
glycerin and chloroform and their combinations can be employed as
well as other materials.
For parenteral administration, solutions or suspensions of these
compounds in sesame or peanut oil or aqueous propylene glycol
solutions, as well as sterile aqueous solutions of the soluble
pharmaceutically acceptable salts described herein can be employed.
Solutions of the salts of these compounds are especially suited for
intramuscular and subcutaneous injection purposes. The aqueous
solutions, including those of the salts dissolved in pure distilled
water, also useful for intravenous injection purposes, provided
that their pH is properly adjusted, suitably buffered, made
isotonic with sufficient saline or glucose and sterilized by
heating or by microfiltration.
The dosage regimen in carrying out the methods of this invention is
that which insures maximum therapeutic response until improvement
is obtained and thereafter the minimum effective level which gives
relief. Thus, in general, the dosages are those that are
therapeutically effective in increasing the contractile force of
the heart or in the treatment of cardiac failure. In general, the
oral dose may be between about 0.01 mg/kg and about 50 mg/kg
(preferably in the range of 0.1 to 10 mg/kg), and the i.v. dose
about 0.005 to about 30 mg/kg (preferably in the range of 0.01 to 3
mg/kg), bearing in mind, of course, that in selecting the
appropriate dosage in any specific case, consideration must be
given to the patient's weight, general health, age and other
factors which may influence response to the drug. The drug may be
administered as frequently as is necessary to achieve and sustain
the desired therapeutic response. Some patients may respond quickly
to a relatively large or small dose and require little or no
maintenance dosage. On the other hand, other patients may require
sustained dosing from about 1 to about 4 times a day depending on
the physiological needs of the particular patient. Usually the drug
may be administered orally 1 to 4 times per day. It is anticipated
that many patients will require no more than about one to about two
doses daily.
It is also anticipated that the present invention would be useful
as an injectable dosage form which may be administered in an
emergency to a patient suffering from acute cardiac failure. Such
treatment may be followed by intravenous infusion of the active
compound and the amount of compound infused into such a patient
should be effective to achieve and maintain the desired therapeutic
response.
* * * * *